OPEN Foundation

Ethnobotany

Psilocybin: from ancient magic to modern medicine

Abstract

Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is an indole-based secondary metabolite produced by numerous species of mushrooms. South American Aztec Indians referred to them as teonanacatl, meaning “god’s flesh,” and they were used in religious and healing rituals. Spanish missionaries in the 1500s attempted to destroy all records and evidence of the use of these mushrooms. Nevertheless, a 16th century Spanish Franciscan friar and historian mentioned teonanacatl in his extensive writings, intriguing 20th century ethnopharmacologists and leading to a decades-long search for the identity of teonanacatl. Their search ultimately led to a 1957 photo-essay in a popular magazine, describing for the Western world the use of these mushrooms. Specimens were ultimately obtained, and their active principle identified and chemically synthesized. In the past 10–15 years several FDA-approved clinical studies have indicated potential medical value for psilocybin-assisted psychotherapy in treating depression, anxiety, and certain addictions. At present, assuming that the early clinical studies can be validated by larger studies, psilocybin is poised to make a significant impact on treatments available to psychiatric medicine.

Nichols, D. E. (2020). Psilocybin: from ancient magic to modern medicine. The Journal of Antibiotics, 1-8., doi.org/10.1038/s41429-020-0311-8
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Salvia divinorum: from recreational hallucinogenic use to analgesic and anti-inflammatory action

Abstract

Salvia divinorum is a herbal plant native to the southwest region of Mexico. Traditional preparations of this plant have been used in illness treatments that converge with inflammatory conditions and pain. Currently, S. divinorum extracts have become popular in several countries as a recreational drug due to its hallucinogenic effects. Its main active component is a diterpene named salvinorin A (SA), a potent naturally occurring hallucinogen with a great affinity to the κ opioid receptors and with allosteric modulation of cannabinoid type 1 receptors. Recent biochemical research has revealed the mechanism of action of the anti-inflammatory and analgesic effect of SA at the cellular and molecular level. Nevertheless, because of their short-lasting and hallucinogenic effect, the research has focused on discovering a new analogue of SA that is able to induce analgesia and reduce inflammation with a long-lasting effect but without the hallucinatory component. In this review, we explore the role of S. divinorum, SA and its analogues. We focus mainly on their analgesic and anti-inflammatory roles but also mention their psychoactive properties.

Coffeen, U., & Pellicer, F. (2019). Salvia divinorum: from recreational hallucinogenic use to analgesic and anti-inflammatory action. Journal of pain research12, 1069., 10.2147/JPR.S188619

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Metabolite Profiling of Antiaddictive Alkaloids from Four Mexican Tabernaemontana Species and the Entheogenic African Shrub Tabernanthe iboga (Apocynaceae)

Abstract

Ibogaine and other ibogan type alkaloids present anti-addictive effects against several drugs of abuse and occur in different species of the Apocynaceae family. In this work, we used gas chromatography-mass spectrometry (GC/MS) and principal component analysis (PCA) in order to compare the alkaloid profiles of the root and stem barks of four Mexican Tabernaemontana species with the root bark of the entheogenic African shrub Tabernanthe iboga. PCA demonstrated that separation between species could be attributed to quantitative differences of the major alkaloids, coronaridine, ibogamine, voacangine, and ibogaine. While T. iboga mainly presented high concentrations of ibogaine, Tabernaemontana samples either showed a predominance of voacangine and ibogaine, or coronaridine and ibogamine, respectively. The results illustrate the phytochemical proximity between both genera and confirm previous suggestions that Mexican Tabernaemontana species are viable sources of anti-addictive compounds.

Krengel, F., Chevalier, Q., Dickinson, J., Santoyo, J. H., & Reyes-Chilpa, R. (2019). Metabolite Profiling of Antiaddictive Alkaloids from Four Mexican Tabernaemontana Species and the Entheogenic African Shrub Tabernanthe iboga (Apocynaceae). Chemistry & biodiversity., 10.1002/cbdv.201800506
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Iterative l-Tryptophan Methylation in Psilocybe Evolved by Subdomain Duplication

Abstract

Psilocybe mushrooms are best known for their l-tryptophan-derived psychotropic alkaloid psilocybin. Dimethylation of norbaeocystin, the precursor of psilocybin, by the enzyme PsiM is a critical step during the biosynthesis of psilocybin. However, the “magic” mushroom Psilocybe serbica also mono- and dimethylates l-tryptophan, which is incompatible with the specificity of PsiM. Here, a second methyltransferase, TrpM, was identified and functionally characterized. Mono- and dimethylation activity on l-tryptophan was reconstituted in vitro, whereas tryptamine was rejected as a substrate. Therefore, we describe a second l-tryptophan-dependent pathway in Psilocybe that is not part of the biosynthesis of psilocybin. TrpM is unrelated to PsiM but originates from a retained ancient duplication event of a portion of the egtDB gene that encodes an ergothioneine biosynthesis enzyme. During mushroom evolution, this duplicated gene was widely lost but re-evolved sporadically and independently in various genera. We propose a new secondary metabolism evolvability mechanism, in which weakly selected genes are retained through preservation in a widely distributed, conserved pathway.

Blei, F., Fricke, J., Wick, J., Slot, J. C., & Hoffmeister, D. (2018). Iterative l‐Tryptophan Methylation in Psilocybe Evolved by Subdomain Duplication. ChemBioChem19(20), 2160-2166., 10.1002/cbic.201800336.
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Production Options for Psilocybin: Making of the Magic

Abstract

The fungal genus Psilocybe and other genera comprise numerous mushroom species that biosynthesize psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine). It represents the prodrug to its dephosphorylated psychotropic analogue, psilocin. The colloquial term “magic mushrooms” for these fungi alludes to their hallucinogenic effects and to their use as recreational drugs. However, clinical trials have recognized psilocybin as a valuable candidate to be developed into a medication against depression and anxiety. We here highlight its recently elucidated biosynthesis, the concurrently developed concept of enzymatic in vitro and heterologous in vivo production, along with previous synthetic routes. The prospect of psilocybin as a promising therapeutic may entail an increased demand, which can be met by biotechnological production. Therefore, we also briefly touch on psilocybin’s therapeutic relevance and pharmacology.

Fricke, J., Lenz, C., Wick, J., Blei, F., & Hoffmeister, D. (2018). Production Options for Psilocybin: Making of the Magic. Chemistry–A European Journal., 10.1002/chem.201802758

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Dark Classics in Chemical Neuroscience: Mescaline

Abstract

Archeological studies in the United States, Mexico, and Peru suggest that mescaline, as a cactus constituent, has been used for more than 6000 years. Although it is a widespread cactus alkaloid, it is present in high concentrations in few species, notably the North American peyote ( Lophophora williamsii) and the South American wachuma ( Trichocereus pachanoi, T. peruvianus, and T. bridgesii). Spanish 16th century chroniclers considered these cacti “diabolic”, leading to their prohibition, but their use persisted to our days and has been spreading for the last 150 years. In the late 1800s, peyote attracted scientific attention; mescaline was isolated, and its role in the psychedelic effects of peyote tops or “mescal buttons” was demonstrated. Its structure was established by synthesis in 1929, and alternative routes were developed, providing larger amounts for pharmacological and biosynthetic research. Although its effects are attributed mainly to its action as a 5-HT2Aserotonin receptor agonist, mescaline binds in a similar concentration range to 5-HT1A and α2A receptors. It is largely excreted unchanged in human urine, and its metabolic products are apparently unrelated to its psychedelic properties. Its low potency is probably responsible for its relative neglect by recreational substance users, as the successful search for structure-activity relationships in the hallucinogen field focused largely on finding more potent analogues. Renewed interest in the possible therapeutic applications of psychedelic drugs may hopefully lead to novel insights regarding the commonalities and differences between the actions of individual classic hallucinogens.
Cassels, B., & Sáez-Briones, P. (2018). Dark Classics in Chemical Neuroscience: Mescaline. ACS chemical neuroscience. 10.1021/acschemneuro.8b00215
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Integrating Psychedelic Medicines and Psychiatry: Theory and Methods of a Model Clinic

Abstract

The past two decades has seen a significant increase in both popular and scientific interest in psychedelic substances and plants as therapeutics for mental illness, addictions, and psychospiritual suffering. Current psychiatric practice privileges a biological paradigm in which the brain is considered the locus of mental illness and symptom-focused treatments are delivered to patients as passive recipients. In contrast, a psychedelic healing paradigm, constructed through examination of different ontologic understandings of plant medicines, is based on a complex multidimensional perspective of human beings and their suffering. This paradigm actively engages the sufferer in addressing root causes of illness through healing on multiple levels of existence, including spiritual and energetic domains. Numerous theoretical, methodological, and ethical challenges complicate the integration of the psychedelic healing paradigm into psychiatric practice. These include developing coherent therapeutic narratives that account for the complex processes by which psychedelic healing occurs and overcoming reductionist tendencies in the medical sciences. Tasked with overcoming such challenges, a model clinic is proposed that seeks to implement and study the psychedelic healing paradigm in a critical, interdisciplinary, and reflexive manner. Such “critical paradigm integration” would employ multimodal patient formulation and treatments, as well as a range of knowledge generation and sharing practices. Outcomes-oriented research would seek to establish an evidence base for the model, while critical dialogues would advance understandings of psychedelic substances and plants and related practices more generally. The clinic would serve as proof of concept for a new model of studying, conceptualizing, and treating mental illness.

Sloshower, J. (2018). Integrating Psychedelic Medicines and Psychiatry: Theory and Methods of a Model Clinic. Plant Medicines, Healing and Psychedelic Science: Cultural Perspectives, 113-132. 10.1007/978-3-319-76720-8_7
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Psychedelic Naturalism and Interspecies Alliance: Views from the Emerging Do-It-Yourself Mycology Movement

Abstract

Do-it-yourself (DIY) mycology is a movement that has emerged in the last decade in North America. DIY mycologists specialize in easy and accessible methods of mushroom cultivation and mycological experimentation and mobilize a discourse of alliance with the fungal kingdom. They draw primarily on home cultivation methods innovated by Psilocybe cultivators in the 1970s and on creative applications popularized by commercial mycologist and psychedelic enthusiast Paul Stamets in the 2000s. As a counterpoint to the newfound visibility and legitimacy of lab-synthesized psilocybin in clinical psychiatry, DIY mycology exemplifies an alternate history of this multispecies engagement. Drawing on ethnographic fieldwork in the San Francisco Bay Area and the Pacific Northwest, this chapter begins with the tacit premise of the psychedelic/entheogenic movement that the use of psychedelics fosters ecological concern. Many DIY mycologists express biocentric ethics and eco-spiritual principles, but interviews revealed a diverse and nuanced relationship to psychedelics. I argue that DIY mycology is best understood as an interspecies (or cross-kingdom) engagement that is part of an emergent ecological ethics and deep ecology worldview, one that subsumes psychedelic experiences as one manifestation of that engagement. DIY mycology exemplifies how the spread of mycological know-how, fascination, and enthusiasm has fostered an engagement with fungi that extends far beyond psychedelics. To understand this engagement, I contextualize it within wider social and cultural shifts, particularly those that reformulated our practical, ethical, and conceptual relationship with the natural world. This movement attests to the existence of multiple means to enact these ethics and to foster meaningful relationality with nonhuman life in contemporary North American society and culture.

Steinhardt, J. (2018). Psychedelic Naturalism and Interspecies Alliance: Views from the Emerging Do-It-Yourself Mycology Movement. Plant Medicines, Healing and Psychedelic Science: Cultural Perspectives, 167-184. 10.1007/978-3-319-76720-8_10
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Plant Knowledges: Indigenous Approaches and Interspecies Listening Toward Decolonizing Ayahuasca Research

Abstract

The ayahuasca research community is familiar with the concept of plant intelligences; however, they have yet to be adequately accounted for by commonly used research practices. This chapter is a call to examine the ontological and epistemological assumptions that underlie research practices and how these practices and assumptions may reinforce hierarchies of knowledge and animacy. The first part of this chapter describes some absences created by following a “methods as usual” approach when researching ayahuasca, based on ethnographic fieldwork at the World Ayahuasca Conference in 2016 (AYA2016). This highlights the need for researchers to acknowledge the methodological, disciplinary, and identity-based limitations on our abilities to produce and represent certain knowledges. Secondly, this chapter is a call to seriously and humbly engage with Indigenous sciences and epistemologies. This requires an honest reckoning with how research has contributed to colonial appropriation and marginalization of Indigenous knowledges. Indigenous ways of knowing have precedent for collaborating with teacher plants in producing knowledge and have much to contribute to discourse on multispecies perspectives. Lastly, I discuss possibilities for including multispecies sensibilities and Indigenous standpoints in research practices to create more collaborative and decolonial knowledges.

Dev, L. (2018). Plant Knowledges: Indigenous Approaches and Interspecies Listening Toward Decolonizing Ayahuasca Research. Plant Medicines, Healing and Psychedelic Science: Cultural Perspectives, 185-204. 10.1007/978-3-319-76720-8_11
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Undiscovering the Pueblo Mágico: Lessons from Huautla for the Psychedelic Renaissance

Abstract

The people of the Sierra Mazateca region of Mexico became internationally known in the 1950s for their ritual use of psilocybin mushrooms, and the Mazatec town of Huautla became a destination for mushroom seeking visitors. This chapter provides an overview of changing Mazatec and “outsider” discourses about mushrooms and the Sierra Mazateca over the last 60 years. It argues that “outsider” representations of the Sierra Mazateca and mushroom use—whether framed in terms of spiritual journeys or scientific research—tend to recapitulate some consistent patterns common to other forms of cultural tourism that owe more to the role of substances in marking distinctive cultural identities than to the effects of the substances themselves. It concludes by suggesting lessons from this history for the current moment, in which a discourse framing the use of psychedelic substances through universalizing narratives of science and individual health is becoming ascendant.

Feinberg, B. (2018). Undiscovering the Pueblo Mágico: Lessons from Huautla for the Psychedelic Renaissance. Plant Medicines, Healing and Psychedelic Science: Cultural Perspectives, 37-54. 10.1007/978-3-319-76720-8_3
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